Background: Reports suggest a potential association between coronavirus disease 2019 (COVID-19) vaccines and acute central nervous system (CNS) inflammation. Objective: The main objective of this study is to describe features of acute CNS inflammation following COVID-19 vaccination. Methods: A retrospective observational cohort study was performed at the BARLO MS Centre in Toronto, Canada. Clinicians reported acute CNS inflammatory events within 60 days after a COVID-19 vaccine from March 2021 to August 2022. Clinical characteristics were evaluated. Results: Thirty-eight patients (median age 39 (range: 20–82) years; 60.5% female) presented within 0–55 (median 15) days of a receiving a COVID-19 vaccine and were diagnosed with relapsing remitting multiple sclerosis (MS) ( n = 16), post-vaccine transverse myelitis ( n = 7), clinically isolated syndrome ( n = 5), MS relapse ( n = 4), tumefactive demyelination ( n = 2), myelin oligodendrocyte glycoprotein antibody disease ( n = 1), neuromyelitis optica spectrum disorder ( n = 1), chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids ( n = 1) and primary autoimmune cerebellar ataxia ( n = 1). Twenty-two received acute treatment and 21 started disease-modifying therapy. Sixteen received subsequent COVID-19 vaccination, of which 87.5% had no new or worsening neurological symptoms. Conclusion: To our knowledge, this is the largest study describing acute CNS inflammation after COVID-19 vaccination. We could not determine whether the number of inflammatory events was higher than expected.